Many investigators have shown that adenoviral (Ad) vectors expressing the bone morphogenetic protein BMP2 can enhance fracture repair by eliciting bone formation that closely resembles the normal process, in contrast to results obtained with direct injection of the recombinant protein. Delivery of BMP2 via an Ad vector is therefore an attractive strategy for improving bone repair, which currently is delayed or unsuccessful in 5-10% of fracture cases. A major challenge is to produce a safe osteoblast-targeted vector that does not recognize cells expressing the widespread adenovirus, CAR, the usual route by which adenoviruses infect mammalian cells. This proposal seeks to increase the specificity and safety of Ad vectors by modifying the viral fiber protein (Aim 1) so that it no longer binds to CAR, but instead recognizes the OST-PTP protein on osteoblasts (Aim 2). These objectives will be pursued by ablating critical amino acid sequences in the fiber DG loop and monitoring cells for evidence of infection through the CAR-binding pathway, and by constructing vectors whose fiber carries both the CAR-binding sequence deletion and an OST-PTP-specific antibody sequence and then assessing their ability to target osteoblasts in vitro and in vivo. Vectors emerging from these studies will be prime candidates for insertion of BMP2 or other therapeutic genes with relevance to bone disease. Given the applicant's experience in adenoviral vector design and translational research in university and pharmaceutical settings, the prospects for a successful outcome of this project appear high.